The overall goal of this proposal is to determine if lentiviral variants that emerge when AIDS develops in the host are more pathogenic than viruses present in the early, asymptomatic stages of infection. If so, we will define the molecular determinants of pathogenicity, and we will begin to study the biochemical basis for differences in phenotype between the early and late variants. HIV and SIV are lentivirus that infect and cause AIDS in humans and macaques, respectively. During the course of both human and simian AIDS, the viruses isolated from individuals late in infection tend to be more virulent to cells in culture than viruses in the early stages of infection. the extracellular envelope (env) glycoprotein is a key determinant of this change in phenotype. Simian AIDS has been experimentally induced with molecularly cloned SIV, providing a system to study virus variation as it relates to disease progression starting from a genetically defined virus. We have identified two regions of extensive variation in the SIV envelope gene as macaques progress to AIDS following inoculation with a molecular clone of SIV. We propose to complete a rigorous examination of the SIV env gene variants, including analysis of tissue-specific variants, so that we can identify particular viruses whose presence correlates with development of AIDS. Chimeric viruses will be constructed that incorporate the env gene of variants representing the viruses most prevalent when disease develops. The functional, immunogenic and pathogenic properties of these viruses will be compared to the original molecular clone of SIV from which they arose. In studies of SIV env variation, a consistent pattern of change in the env gene was identified during the course of infection. We will determine if the pattern of change characteristic of SIV env variants that predominate in macaques with AIDS is also characteristic of HIV variants associated with the later stages of human AIDS. The studies proposed in this application, which include analysis of the molecular and biological properties of the variant that are selected for in the host, will provide insight into the mechanisms underlying progression to AIDS.